KR20050106336A - Novel chromen-2-one based hydroxamic acid derivatives, having anti-inflammatory activity, preparation thereof and composition containing the same for treating inflammatory disease - Google Patents

Abstract

The present invention provides novel compounds having excellent anti-inflammatory activity, methods for their preparation and compositions for the treatment of inflammatory diseases comprising the same.

The compound according to the present invention exhibits a strong inhibitory activity against tumor necrosis factor-α converting enzyme (TNF-α converting enzyme), whereby the composition comprising the same can be used as a medicament for the treatment of inflammatory diseases, especially arthritis.

Description

Novel Chromen-2-one based hydroxamic acid derivatives, having anti-inflammatory activity, preparation according to composition containing the same for treating inflammatory disease}

The present invention relates to a chromium-2-one hair nucleophilic acid derivative having anti-inflammatory activity, a method for preparing the same, and a composition for the treatment of an inflammatory disease comprising the same.

Inflammation is a normal condition in the body that responds to wounds or diseases. Injured or diseased joints are accompanied by swelling, pain, and stiff joints. Inflammation usually occurs in the case of arthritis, but sometimes results in a long and permanent disability.

In general, arthritis, or inflammatory disease of joints, occurs in various forms, such as rheumatoid arthritis (hereinafter referred to as RA) and joint inflammation related diseases.

Arthritis is a chronic progressive disease, characterized by inflammatory changes, especially in the synovial membrane of the lining of the articular capsule, causing swelling and pain in the joints of the whole body and, in severe cases, becoming a physically handicapped person. Arthritis diseases such as RA are also progressive and develop joint disorders such as deformation and joint instability, often causing severe physical disorders due to lack of effective treatment and continued exacerbation.

Osteoarthritis (hereinafter referred to as OA) has a complex multifactorial causality and considerable diversity in its clinical manifestations, but an important factor causing OA is known as synovial inflammation. In addition, synovial injury may promote dissociation of proteoglycans (PG) as a result of the interaction between synovial cells and chondrocytes, and activated synovial cells may induce a number of soluble factors that may lead to loss of articular cartilage ( For example, interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) and prostaglandins). Direct injury of chondrocytes also promotes the production of matrix metalloproteinase (MMP) activity (eg collagenase, stromelysin and gelatinase) and various inflammatory mediators. In any case, the reduced functionality of articular cartilage results in OA disease development. Depletion of PG from OA joint tissue imparts abnormal mechanical stress to chondrocytes, subchondral osteoblasts and synovial cells as the elasticity imparted by the PG to cartilage is reduced.

Osteoarthritis and rheumatoid arthritis are destructive diseases of articular cartilage characterized by local erosion of the cartilage surface. For example, studies have shown that articular cartilage from the femoral head of an OA patient has decreased the introduction of radioisotope-labeled sulfate compared to the control group, suggesting an increased rate of cartilage degradation in OA. (Mankin et al ., J. Bone Joint Surg . 52A , pp 424-434, 1970). Mammalian cells have four types of proteolytic enzymes: serine, cysteine, aspartic acid and metalloproteinases. Evidence has shown that metalloproteinases are responsible for the extracellular matrix degradation of articular cartilage in OA and PA patients. Increased activity of collagenase and stromelysin has been found in cartilage of OA patients, which activity is correlated with the depth of the lesion (Mankin et al., Arthritis Rhenum . 21 , pp761-766, 1978), (Woessner et al. , Arthritis Rhenum . 26 , pp63-68, 1983) and ( Ibid . 27 , pp305-312, 1984). In addition, agrecanase (which has recently been identified as having metalloproteinase enzyme activity) has been found in OA and RA patients and has been demonstrated to provide specific cleavage products of proteoglycans (Lohmander LS et al . , Arthritis Rheum . 36 , pp 1214-1222, 1993).

Tumor necrosis factor (TNF) is a cytokine bound to cells and is processed from 26 kD precursor forms to 17 kD active forms. TNF has been shown to be the primary regulator of acute phase responses similar to those observed during inflammation, fever, and acute infections and shock in humans and animals. Excess TNF has been found to lead to death. Currently, the use of specific antibodies to block the effects of TNF can lead to rheumatoid arthritis, insulin-independent diabetes (Lohmander LS et al. Arthritis Rheum . 36 , pp1214-1222, 1993), Crohn's disease (Macdonald T. et al. Clin). Exp. Immunol. 81 , p301, 1990), have been shown to be beneficial in a number of situations, including autoimmune diseases.

Thus, compounds that inhibit the production of TNF are of therapeutic importance in the treatment of inflammatory diseases. Recently, matrix metalloproteinases or metalloproteinases (later known as Tumor necrosis factor-α convertase (TNF-C)) as well as other MPs are active in their inactive form. It has been found that it can be converted to the form (Gearing et al., Nature , 370 , p555, 1994). Therefore, inhibiting this conversion and thus inhibiting the release of active TNF-α from the cells will be an important mechanism in the treatment of inflammatory diseases.

Because overproduction of TNF is prominent in many diseases characterized by MMP-mediated tissue degradation, compounds that inhibit both MMP and TNF production have particular advantages even in diseases involving both mechanisms.

Hydroxamate and carboxylate based MMP inhibitors disclose N-carboxyalkylpeptidyl compounds in WO 92/213260 and WO 90/05716 and WO 92/13831. A base collagenase inhibitor is disclosed, and International Publication No. 94/02446 discloses a metalloproteinase inhibitor which is a natural amino acid derivative of the formula: International Publication No. 95/09841 also describes compounds that are hydroxamic acid derivatives and inhibitors of cytokines, and British Patent Publication Nos. 2268934 and International Publication No. 94124140 disclose hydrophiles of MMPs as inhibitors of TNF production. Is disclosed.

Traditionally, arthritis has been shown to include steroids such as cortisone and other corticosteroids, nonsteroidal anti-inflammatory agents such as aspirin, pyroxicam and indomethacin, gold agonists such as orothioactive acid, chloroquinones and D-phenicamine. It has been treated with chemotherapy using a variety of agents including anti-rheumatic agents, gout inhibitors such as colchicine and immunosuppressants such as cyclophosphamide, azathioprine, methotrexate and levamisol.

However, the above-mentioned treatments are not fundamental treatments, and steroid hormones have been widely used as known as arthritis treatments, but as their side effects become clear, their use has become difficult.

In addition, arthritis, especially chronic rheumatoid arthritis, causes severe pain in patients, so be sure to take anti-inflammatory drugs, etc. Until now, aspirin and betazoline drugs have been widely used as drugs to alleviate these pains or remove joint swelling. Has been used. However, aspirin and the like have a fatal effect on the stomach, so it is difficult to continue taking the amount needed to treat arthritis.

Existing chemotherapeutic agents have drawbacks such as side effects that hinder the long-term use of the drugs, lack of anti-inflammatory effects, and lack of efficacy on arthritis that has already occurred, and now indomethacin has excellent analgesic effects in the treatment of arthritis And furphenic acid and various non-steroidal anti-inflammatory agents are used in preparation.

Therefore, there is a need for a solution to these problems and the development of arthritis therapies that have symptomatic effects on acute inflammatory symptoms and pain, and most of the arthritis drugs currently in use have some differences or personal differences. It is very important to develop medicines with fewer side effects, because they have side effects, and especially for the treatment of rheumatoid arthritis, it is necessary to take the drug for a long time.

The inventors of the present invention, while continuing to develop a substance exhibiting a strong inhibitory activity against the production of TNF-α by using a tumor necrosis Factor-α convertase as a point of action, the compound of the present invention It was found that this exhibited excellent inhibitory activity of TNF-α production, and completed the present invention.

It is an object of the present invention to provide an anti-inflammatory material, a method for preparing the same, and a composition for treating an inflammatory disease including the same, which exhibits an excellent anti-inflammatory effect.

In order to achieve the above object, the present invention provides a compound having the structure of formula (I) or a pharmacologically acceptable salt thereof, which is useful for the treatment of an inflammation related disease:

(Ⅰ)

Where

X is -OH, -NHOH, or NHO-R ', R' is a lower alkyl group or benzyl group;

n is an integer from 1 to 4;

Y is O, S, or N;

R ₁ is a hydrogen atom, a lower alkyl group or a benzyl group;

R ₂ is C ₁ to C ₄ lower alkyl, C ₁ to C ₄ lower alkoxy;

R ₃ to R ₆ are each independently a hydrogen atom, nitro, halogen, amine, acetamide, carboamide, sulfonamide group, C ₁ to C ₄ lower alkyl, C ₁ to C ₇ unsubstituted or substituted An alkoxy group or a substituent thereof may be fused to each other to form a 3- to 5-membered aromatic ring of heteroaryl substituted with an aromatic or hetero atom, and R ″ is a 5- to 6-membered ring substituted with an aryl group or a hetero atom. .

General formula Among the compounds (I), X is -OH and -NHOH, Y is oxygen or sulfur atom, R ₁ is hydrogen atom, methyl or ethyl group, R ₂ is methyl, ethyl group R3 to R ₆ is a methoxy or ethoxy compound group, R ₃ to R ₆ are hydrogen atoms, halogen, C ₁ to C ₄ lower alkoxy or phenyl group substituted with a C ₁ to C ₇ alkoxy group or a three-membered group formed by mutual fusion Group of compounds which are heteroaromatic rings and salts thereof.

General formula Particularly preferred groups of compounds in (I) include the following compounds and pharmaceutically acceptable salts thereof:

3- (6-bromo-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (1d),

3- (6-chloro-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (2d),

N-hydroxy-3 (6-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (3d),

N-hydroxy-3- (7-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (4d),

N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3yl) -propionamide (5d),

3- (6-t-butyl-2-oxo-2H-chromen-3yl) -N-hydroxy-propionamide (6d),

N-hydroxy-3- (2-oxo-2H-chromen-3yl) -propionamide (7d),

N-hydroxy-3- (3-oxo-3H-benzo [f] chromen-2-yl) -propionamide (8d),

3- (8-ethoxy-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (9d),

3- (6-bromo-2-oxo-2H-chromen-3-yl) -butyric acid (10i),

N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -butylamide (11j),

Synthesis of N-hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide (12q),

N-hydroxy-3- (6-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (14x),

3- (6-ethoxy-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (15x),

3- (6-benzyloxy-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (16x),

N-hydroxy-3- (2-oxo-6-phenethyloxy-2H-chromen-3-yl) -propionamide (17x),

N-hydroxy-3- (2-oxo-6- (3-phenyl-propoxy) -2H-chromen-3-yl] -propionamide (18x),

N-hydroxy-3- (2-oxo-6- (3-phenyl-butoxy) -2H-chromen-3-yl] -propionamide (19x),

N-hydroxy-3- (4-methoxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (21aj),

3- (4-ethoxy-6-methyl-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (22j),

N-hydroxy-3- (4-isopropoxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (23j),

3- (4-benzyloxy-6-methyl-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (24j),

N-hydroxy-4- (6-methoxy-2-oxo-2H-chromen-3-yl) -butylamide (25at),

5- (6-methoxy-2-oxo-2H-chromen-3-yl) -pentanoic acid hydroxyamide (26at),

N-hydroxy-2- (6-methoxy-2-oxo-2H-chromen-3-yl) -acetamide (27at),

N-hydroxy-3- (6-methoxy-2-oxo-2H-thiochromen-3-yl) propionamide (29bd),

N-hydroxy-3- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) -propionamide (30 bm),

N-hydroxy-3- (6-methoxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl) propionamide (31bo),

3- (1-Benzyl-6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) -N-hydroxy-propionamide (32bo).

The present invention also provides a method for preparing the compound of Formula (I) and a pharmaceutical composition comprising the same as an active ingredient.

The present invention also provides a compound having the structure of formula (II) or a pharmacologically acceptable salt thereof, useful for the treatment of inflammation related diseases:

(Ⅱ)

Where

dotted line( ) Means a single bond or a double bond;

X is -OH, -NHOH, or NHO-R ', R' is a lower alkyl group or benzyl group;

Y is O, S, or N;

R ₁ is a hydrogen atom, a lower alkyl group or a benzyl group;

R ₂ is C ₁ to C ₄ lower alkyl, C ₁ to C ₄ lower alkoxy;

R ₃ to R ₆ are each independently a hydrogen atom, nitro, halogen, amine, acetamide, carboamide, sulfonamide group, C ₁ to C ₄ lower alkyl, C ₁ to C ₇ unsubstituted or substituted Or a lower alkoxy group or a substituent thereof may be fused to each other to form a 3- to 5-membered aromatic ring of heteroaryl substituted with an aromatic or hetero atom, and R ″ is a 5- to 6-membered ring substituted with an aryl group or a hetero atom. ;

R ₇ to R ₉ are each independently a hydrogen atom, a lower alkyl group substituted with a C ₁ to C ₇ alkyl, aryl group or heteroaryl group, provided that both are not hydrogen atoms at the same time.

General formula Among the compounds (II), preferably, X is -OH, -NHOH, Y is an oxygen or sulfur atom, R ₁ is a hydrogen atom, a methyl or ethyl group, R ₂ is methyl, ethyl, R3 to R ₆ is a methoxy or ethoxy compound group, R ₃ to R ₆ are hydrogen atoms, halogen, C ₁ to C ₄ lower alkoxy or phenyl group substituted with a C ₁ to C ₇ alkoxy group or a ternary member formed by fusion of these substituents heteroaryl direction Whanin group of compounds, R ₇ to R ₉ is a group a compound and salts thereof, lower alkyl group of C ₁ to C _4.

General formula Particularly preferred groups of compounds in (II) include the following compounds and pharmaceutically acceptable salts thereof:

N-hydroxy-2-methyl-3- (2-oxo-2H-chromen-3-yl) propionamide (13q),

2-benzyl-N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (20af),

N -hydroxy-3- (6-methoxy-2-oxo- 2H -chromen-3-yl) -acrylamide (28ay).

The present invention also provides a method for preparing the compound of Formula (II) and a pharmaceutical composition comprising the same as an active ingredient.

The compounds of the present invention represented by the above general formula (I) or (II) may be prepared with pharmaceutically acceptable salts and solvates according to conventional methods in the art.

As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.

Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of formula (I) or (II) above include salts of acidic or basic groups which may be present in compounds of formula (I) or (II) unless otherwise indicated . For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and methods or processes for preparing salts known in the art It can be prepared through.

In addition, the compounds of the general formula (I) or (II) above have asymmetric centers and therefore may exist in different enantiomeric forms, and all the optical isomers of the compounds of the general formula (I) or general formula (II) and R or S type stereoisomers and mixtures thereof are also included within the scope of the present invention. The present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods or processes for the separation of isomers known in the art.

Another object of the present invention is to provide a method for preparing the compound of Formula (I) or (II), which may be chemically synthesized by the method shown in Schemes below, but is not limited thereto.

The following reaction schemes represent the preparation steps of representative compounds of the present invention. The various compounds of the present invention may be prepared by small changes such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 to 11. Can be. Some compounds of the present invention have been synthesized according to procedures not included in the scope of Schemes 1-11, and detailed synthesis procedures for these compounds are described in their respective examples.

Scheme (1) shows a three-step process for preparing compound (d) using aldehyde (a) as a starting material that can be easily obtained commercially.

In the first step, compound (b) is prepared by reacting compound (a) with 4-chlorocarbonyl-butyric acid methyl-1-ester in an organic solvent in the presence of triethylamine base. In this case, dichloromethane or the like may be used as the organic solvent, and diethylisopropylamine or the like may be used in addition to the triethylamine base. Triethylamine base can be used in 2 to 3 equivalents based on the starting compound (a), and their reaction can be carried out at room temperature to 0 ℃. In the second step, the compound (b) obtained in the first step is subjected to 1,8-diazabicyclo [5,4,0] undec-7-ene (1,8-Diazabicyclo [5,4,0] undec- 7-ene, DBU) to react in an organic solvent to prepare compound (c). At this time, toluene, xylene, benzene or the like can be used as the organic solvent. At this time, the amount of 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) may be used in an amount of 2 to 3 equivalents based on compound (b), and their reaction may be performed at room temperature. It may be carried out at a temperature in the range from to 110 ℃. In the third step, the compound (c) may be reacted with an amine salt in an alcohol solvent to obtain a compound (e) in which the substituent X in the compound of formula (I) according to the present invention is -NHOH. The amine salt is preferably potassium hydroxyamide, the amount of which is preferably used in an amount of 2 to 3 equivalents based on compound (d), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C.

Scheme (2) is a three-step preparation process for preparing compound (g) using a commercially available diester (e) as a starting material and the same process as in Scheme (1). This is the process of obtaining compound (i) which can be obtained in the same manner as. In addition, the preparation process for obtaining compound (i) in which X is -OH is shown in the compound of formula (I) according to the present invention.

Compound (e) is reacted with hydroxide in an organic solvent such as methanol to give compound (f). At this time, lithium hydroxide is preferably used as the hydroxide which can be used for the reaction, and its amount is preferably used in the range of 2 to 3 equivalents relative to compound (e), and their reaction is a temperature in the range of room temperature to 0 ° C. Preference is given to performing at. The obtained compound (f) is dissolved in an organic solvent such as dichloromethane, and then oxalyl chloride and a catalytic amount of dimethylformamide are added to obtain compound (g). The amount used is preferably used in the range of 2 to 3 equivalents relative to compound (f), and their reaction is preferably performed at a temperature in the range of room temperature to 0 ° C. Compound (h) is obtained in two steps using compound (g) and compound (a) obtained in the same manner as in Scheme (1). Compound (h) is reacted with hydroxide in an organic solvent such as methanol to obtain compound (i). At this time, as the hydroxide salt usable for the reaction, barium hydroxide is preferable, and the amount thereof is preferably used in the range of 2 to 3 equivalents relative to compound (h), and their reaction is a temperature in the range of room temperature to 0 ° C. Preference is given to performing at. In the fifth step, the compound (h) may be reacted with an amine salt in an alcohol solvent to obtain a compound (j) in which the substituent X in the compound of formula (I) according to the present invention is -NHOH. The amine salt is preferably potassium hydroxyamide, the amount of which is preferably used in an amount of 2 to 3 equivalents based on compound (h), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C.

Scheme (3) shows a process for producing (q) a compound having a substituent at the alpha position of hydroxyamide from a commercial compound (k).

In the first step, compound (l) is prepared by reacting compound (k) with ethyl acrylate in an organic solvent in the presence of sodium hydride base. At this time, tetrahydrofuran or the like can be used as the organic solvent. Sodium hydride salts may be used in an amount of 1.2 to 1.5 equivalents based on the starting compound (k), and their reaction is performed at 0 ° C. to form an anion of the starting compound (k), followed by reaction with an acrylate at room temperature. It is suitable. In the second step, the compound (n) is prepared under the same conditions as the method used for the compound (l) obtained in the first step in the first step. In the third step, the compound (n) is reacted with a silylamine salt at low temperature (-78 ° C) in a tetrahydrofuran solvent and then reacted with ethyl iodide to prepare a compound (o). At this time, the room temperature is appropriate at low temperature (-78 ℃). In the fourth step, compound (p) can be obtained through a two step process. First, the silyl group of the compound (o) is removed from the hydroxy group using tetrabutylammonium fluoride, and tetrahydrofuran is suitable as a solvent used at this time. Tetrabutylammonium fluoride may be used in an amount of 1.2 to 1.5 equivalents based on the starting material (o), and their reaction is preferably performed at 0 ° C. Second, it is appropriate to use xylene, which is an organic solvent suitable for the high temperature reaction required for the cyclization reaction, to the material obtained in the first step, and the reaction temperature is performed at 140 ° C., which is a temperature higher than the boiling point of the solvent, xylene. Compound (p) can be obtained. In the fifth step, the compound (p) may be reacted with an amine salt in an alcohol solvent to obtain a compound (q) in which the substituent X in the compound of formula (II) according to the present invention is -NHOH. The amine salt is preferably potassium hydroxyamide, the amount of which is preferably used in an amount of 2 to 3 equivalents based on compound (p), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C.

Scheme (4) shows a sixth step of preparation for preparing compound (x) from commercial aldehyde (r) with the same kind of compound as in Scheme (1) above.

In the first step, compound (s) may be reacted with t -butyldimethylsilyl salt to obtain compound (s). As the salt used in the reaction, imidazole is preferable, and dimethylformamide or dimethyl chloride may be used as the solvent. In the second step, compound (t) is prepared by reacting compound (s) with 4-chlorocarbonyl-butyric acid methyl-1-ester in an organic solvent in the presence of triethylamine base. At this time, dichloromethane or the like may be used as the organic solvent, and diethylisopropylamine or the like may be used as the triethylamine base. Triethylamine base may be used in an amount of 2 to 3 equivalents based on compound (s) as a starting material, and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C. In the third step, compound (u) is prepared by reacting compound (t) obtained in step 2 in an organic solvent in the presence of DBU. At this time, toluene, xylene, benzene or the like can be used as the organic solvent. In this case, the amount of DBU may be used in an amount of 2 to 3 equivalents based on compound (t), and their reaction may be performed at a temperature ranging from room temperature to 110 ° C. In the fourth step, compound (v) is prepared by reacting the silyl group of compound (u) with tetrabutylammonium fluoride. At this time, tetrahydrofuran is suitable as a solvent and tetrabutylammonium fluoride may be used in an amount of 1.2 to 1.5 equivalents based on the starting material (u), and the reaction thereof is preferably performed at 0 ° C. In the fifth step, compound (v) is reacted with alkyl halide to obtain compound (w). In the sixth step, the compound (w) may be reacted with an amine salt in an alcohol solvent to obtain a compound (x) in which the substituent X in the compound of formula (I) according to the present invention is -NHOH. The amine salt is preferably potassium hydroxyamide, the amount of which is preferably used in an amount of 2 to 3 equivalents based on the compound (w), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C.

Scheme (5) shows a fifth step for preparing compound (af) from commercial aldehyde (ab) in the same manner as in Scheme (1).

In the first step, the starting material (y) is a process of preparing compound (z) by reacting with an Eshmoser salt. As a solvent used in this simple Mannich reaction, alcohols such as methanol and ethanol are preferable, and benzyl alcohol may be used in addition to simple alcohol. The reaction temperature is suitably about 65 ° C, regardless of the solvent used. In the second step, the compound (z) prepared in the above reaction is reacted with the compound (k) to prepare the compound (aa). The conditions used at this time are used in the same manner as the preparation of the compound (l). Lose. The preparation of another starting material (ac) is necessary to prepare compound (ad). The starting material (ab) is reacted with benzyl bromide to produce compound (ac). Potassium carbonate is suitable as a salt and dimethylformamide as a solvent. The reaction temperature is preferably room temperature, and the amount of salt used is suitably used at least 2 equivalents to the starting material (ab). Compounds (ad), (ae), (af) and the like are subjected to the same conditions as those for producing compounds (n), (p) and (q), respectively.

Scheme (6) shows a third step of preparation for preparing compound (aj) from commercial compound (ag).

In the first step, a compound (ah) is prepared by reacting with a meldrum's acid using a commercially available compound (ag) as a starting material. In addition to the melt acid, the reagents used together include aqueous formaldehyde solution and ammonium acetate, each of which is used in an amount of 1.2 to 1.5 equivalents based on the starting materials. As a solvent, simple alcohols such as methanol ethanol are used, and the reaction temperature is appropriate to the temperature above the boiling point of the solvent used. In the second step, slightly different reaction conditions are used depending on the kind of alkoxy compound to be prepared. In the case of the methoxy compound, compound (ai) is obtained by reaction with trimethylsilyl diazomethane, and the solvent used is a solvent in which benzene and methanol are mixed 4: 1. The reaction temperature is appropriate at room temperature and the reaction time is terminated within about 10 minutes. However, alkoxy compounds other than methoxy may be prepared under slightly different reaction conditions. The starting material (ah) is reacted with an alkyl halide to give compound (ai). At this time, potassium carbonate is suitable as a salt, and acetone is mainly used as a solvent. The reaction temperature is preferably above the boiling point of acetone, and the reaction time is suitably between about 12 hours and 16 hours. In the third step, the compound (ai) may be reacted with an amine salt in an alcohol solvent to obtain a compound (aj) in which the substituent X in the compound of formula (II) according to the present invention is -NHOH. The amine salt is preferably potassium hydroxyamide, the amount of which is preferably used in an amount of 2 to 3 equivalents based on compound (ai), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C.

Scheme (7) shows a fourth step for preparing compound (at) by reacting with commercial aldehyde (ap) and commercial acyl chloride (al) or mono acid (ao) by the above method.

Before starting the first stage reaction, acid chloride (ao) is first prepared and used directly in the first stage reaction. This pre-reaction process is divided into two stages. In the first process, commercially available diacid (am) is reacted with trimethyl diazomethane in a solvent containing 4: 1 of benzene and methanol to react an compound (an). To obtain. The reaction temperature is suitable for room temperature and the reaction time is preferably 10 minutes to 20 minutes. In the second process, the compound (an) is prepared by reacting the compound (an) with barium dioxide in a methanol solvent. In this case, the reaction temperature used is room temperature, and the reaction time is preferably 6 to 8 hours. In the first step, compound (aq) is prepared by reacting compound (ap) with (al) or (ao) in an organic solvent in the presence of triethylamine base. At this time, dichloromethane or the like can be used as the organic solvent, and diethylisopropylamine or the like can be used other than the triethylamine base. Triethylamine base may be used in an amount of 2 to 3 equivalents based on the starting compound (ap), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C. In the second step, the compound (aq) obtained in step 1 is reacted in an organic solvent in the presence of DBU to prepare compound (ar). At this time, toluene, xylene, benzene or the like can be used as the organic solvent. In this case, the amount of DBU may be used in an amount of 2 to 3 equivalents based on compound (aq), and their reaction may be performed at a temperature ranging from room temperature to 110 ° C. In the third step, the compound (ar) is reacted with barium dioxide in a methanol solvent to prepare the compound (as). In this case, the reaction temperature used is room temperature, and the reaction time is preferably 6 to 8 hours. In the fourth step, the compound (as) is reacted with oxalyl chloride in the presence of a catalytic amount of dimethylformamide in a dichloromethane solvent to prepare an acid chloride of the compound (as). The reaction with a salt in a dichloromethane solvent can give compound (at) in which the substituent X in the compound of formula (I) according to the invention is -NHOH. As the amine salt, trimethylsilyl hydroxyamide is preferable, and the amount thereof is preferably used in an amount of 2 to 3 equivalents based on compound (as), and the reaction thereof may be performed at a temperature ranging from room temperature to 0 ° C.

Scheme (8) shows a fourth step for preparing compound (ay) by reacting with commercial aldehyde (ap) and commercial dicarboxylic acid (au).

In the first and second steps, compound (au) is reacted in an alcohol solvent in the presence of inorganic acids such as sulfuric acid and hydrochloric acid to obtain compound (av), and then compound (av) and compound (ap) are reacted in the presence of a base. Compound (aw) is obtained by heating in an organic solvent which does not adversely affect. In this case, a general amine base such as piperidine, triethylamine diethylisopropylamine, and pyridine may be used as the base, and an organic solvent such as ethanol may be used as the organic solvent. The reaction temperature can generally be carried out at room temperature to warm, preferably at room temperature.

In the third step, the ester compound (aw) obtained in step 2 is reacted with hydroxide in the presence of methanol and an aqueous solution to obtain compound (ax). The hydroxide used at this time is preferably sodium hydroxide, potassium hydroxide, barium hydroxide, etc., the amount thereof is preferably used in 2 to 3 equivalents, and their reaction temperature may be performed under cooling to warming, but preferably at room temperature. do.

In the fourth step, the compound (ax) obtained in the above step 3 is combined with a carboxylic acid activating compound such as pentafurophenol and 1- (3-dimethylaminopropyl) -3-methylcarbodiimide hydrochloride (EDCI). The reaction is carried out using a base such as 4-dimethylaminopyridine (DMAP) or the like using an inert organic solvent such as dichloromethane or chloroform, followed by reaction with hydroxylamine in the presence of a base to obtain a compound (ay). The base used in this case may be a common amine base such as piperidine, triethylamine diethylisopropylamine, pyridine, and the like, and the reaction temperature may be generally performed under cold to warm temperature, but preferably at room temperature. Perform.

Scheme (9) shows a fourth step for preparing compound (bd) starting from commercially available thiophenyl (az).

In the first step, compound (az) is an organic solvent (hexane, tetrahydro) that does not adversely affect the reaction in the presence of a base such as N, N, N ', N'-tetramethylenediamine (TMEDA) and n-butyllithium. Using furan, ether, etc.) under cooling to react with dimethylformamide to obtain compound (ba). As the base used in the reaction, common alkyllithium or lithium bistrimethylsilylamide, etc. which are commonly used besides n-butyllithium may be used. The reaction temperature at this time is generally carried out under cold to room temperature.

The method for obtaining compound (bd) using the compound (ba) obtained above is carried out under the same conditions as the method for obtaining compound (d) in compound (a) of Scheme (1).

Scheme (10) is a preparation for preparing a quinoline compound (bm) starting from commercially available 5-hydroxy-2-nitrobenzaldehyde with nitroaldehyde (be) obtained by reacting with iodine methyl in the presence of a base such as potassium carbonate. An eight-step manufacturing process is shown.

In the first step, compound (bf) is reacted with diethylmalonate in the presence of acetic anhydride in the presence of a base to prepare compound (bf). Preferred bases used in the reaction are sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like, and may be performed using an organic solvent (dimethyl sulfoxide, dimethylformamide, etc.) that does not adversely affect the reaction. Preferably, the reaction is carried out without using an organic solvent. The reaction temperature is not particularly limited but is preferably carried out by heating.

In the second step, the compound (bg) is prepared by reacting the compound (bf) obtained in the first step with iron in the presence of an acid. At this time, the acid used may be an inorganic acid such as acetic acid, hydrochloric acid, sulfuric acid, but is preferably performed using acetic acid. The reaction temperature is not particularly limited but is preferably carried out by heating.

In the third step, the ester compound (bg) obtained in the second step is subjected to an ester reduction reaction to prepare an alcohol compound (bh). In this case, the reducing agent used may be a general reducing agent for converting an ester compound into an alcohol compound. Preferably, lithium aluminum hydride, lithium triethyl borohydride, sodium borohydride, borane dimethyl sulfide complex, or the like may be used. The reaction is carried out, and the organic solvent used at this time can be carried out using an organic solvent (anhydrous tetrahydrofuran, ether, dimethylformamide, alcohol, etc.) that does not adversely affect the reaction. The reaction temperature is not particularly limited but is preferably performed at cold to room temperature.

In the fourth step, the compound (bh) obtained in the third step is halogenated to prepare an alcohol compound (bi). In this case, the conversion of the halogen compound generally adversely affects the reaction in the presence of a base such as triethyl amine using a reagent for converting the hydroxyl group to the halogen, for example, tribromo phosphine, tetrabromo methane and the like. Organic solvents (chloroform, dimethylformamide, acetonitrile, etc.) may be used. The reaction temperature is not particularly limited, but is generally performed at cold to room temperature.

In the fifth step, compound (bj) is prepared by reacting compound (bi) obtained in the fourth step with diethyl malonate. The reaction can be carried out using an inert organic solvent such as tetrahydrofuran, ether, dimethylformamide, alcohol, etc. using a base such as sodium hydride, potassium carbonate, sodium ethoxide. The reaction temperature is not particularly limited but is generally performed at room temperature to warm.

In the sixth step, a compound (bk) is prepared by heating the compound (bj) obtained in the fifth step to perform a decarbonation reaction. The reaction is carried out by heating the compound (bj) until there is no starting material under a mixed solution of acetic acid and water.

In the seventh step, the compound (bk) obtained in the sixth step is reacted in methanol using inorganic acids such as sulfuric acid and hydrochloric acid to prepare compound (bl). The reaction temperature is not particularly limited but is generally performed at room temperature to warm.

In the eighth step, the compound (bm) is obtained by using the compound (bl) obtained in the seventh step.

Scheme (11) shows a second step preparation process for preparing quinoline compound (bo) starting from compound (bl) of Scheme (10).

In the first step, compound (bl) obtained in Scheme (10) is reacted with iodine methane or benzyl bromide in the presence of a base to prepare compound (bn). Preferred bases used in the reaction are sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like, which can be carried out using an organic solvent such as dimethyl sulfoxide and dimethyl formamide that does not adversely affect the reaction. The reaction temperature is not particularly limited but is preferably performed at room temperature.

In the second step, the compound (bo) is obtained by using the compound (bn) obtained in the first step, and is carried out under the same conditions as the method for obtaining the compound (d) from the compound (c) of Scheme (1).

Derivatives of the present invention prepared from the above production method, by showing the strong inhibitory activity against the production of NO and TNF-α using the tumor necrosis factor-α conversion enzyme and sialic acid glycotransferase as a point of action shows an excellent anti-inflammatory effect As a result, it is useful for treating inflammation-related diseases.

It exhibits excellent anti-inflammatory effect by showing strong inhibitory activity against tumor necrosis factor-α converting enzyme, which is useful for treating inflammation-related diseases.

The present invention also provides a pharmaceutical composition for the treatment of inflammatory diseases comprising the compound of the general formula (I) or (II) as an active ingredient and a pharmaceutically acceptable carrier.

The compounds of the general formula (I) or (II) of the present invention can be usefully used for the treatment of pain and inflammation caused by inflammatory diseases, especially arthritis. The arthritis includes, for example, rheumatoid arthritis, spondyloarthopathies, gout, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. It includes. In addition, the compounds of the present invention can be used to treat inflammatory symptoms, such as, for example, myositis, gingivitis, synovitis, ankylosing spondylitis, bursitis ( burstitis, burns, wounds, and the like. In addition, the compounds of the present invention are useful for treating inflammatory symptoms associated with diseases such as inflammatory bowel disease, Crohn's disease, Type I diabetes and the like.

Compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.

Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.

Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ), Lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times daily. The compound of the present invention in the composition should be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight relative to the total weight of the total composition.

In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

The pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1 Synthesis of 3- (6-Bromo-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (1d)

Step 1.Synthesis of malonic acid 4-bromo-2-formyl-phenyl ester methyl ester (1b)

To a solution of compound (a) (82 mg, 0.41 mmol) dissolved in dichloromethane, 4-chlorocarbonyl-butyric acid methyl ester (68 mg, 0.41 mmol) and triethylamine (83 mg, 0.82 mmol) were added. It was. The resulting solution was stirred at room temperature for 4 hours, washed with 10% hydrochloric acid, and the organic layer was extracted with ethyl acetate. The resulting organic layer was washed again with saturated sodium bicarbonate solution and then extracted again with ethyl acetate. The solution was washed again with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the solution was distilled at low atmospheric pressure and the compound thus obtained was used directly in the next reaction.

Step 2. Synthesis of 3- (6-Bromo-2-oxo-2H-chromen-3-yl) -propionic acid methyl ester (1c)

After dissolving the residue compound (1b) in toluene solvent, DBU (125 mg, 0.82 mmol) was added, the solution was stirred at 110 ° C. for 12 hours, the temperature was gradually lowered to room temperature, and the solution was distilled at low atmospheric pressure. Was purified by column chromatography method (silica gel column, eluent ethyl acetate / hexane = 1/3) to afford the title compound in 40-45% yield (51 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.53 (s, 1H), 7.53-7.48 (m, 3H), 7.16-7.13 (m, 1H), 3.63 (s, 3H), 2.85 (t, J = 7.0 Hz, 2H), 2.67 (t, J = 6.8 Hz, 2H)

Step 3. Synthesis of 3- (6-bromo-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (1d)

1.7 mol of potassium hydroxy amine solution (34 μL, 0.82 mmol) was added using methanol as a solvent, followed by stirring at room temperature for 1 hour. After completion of the reaction with acetic acid, the resulting solution was distilled at low atmospheric pressure to obtain a residue, which was purified by column chromatography method (silica gel column, eluent: methanol / chloroform = 1/10) to give the title compound 65-80%. Obtained in (83 mg).

¹ H-NMR (CD ₃ OD, 200 MHz) δ 7.66-7.55 (m, 3H), 7.21-7.16 (d, J = 8.7 Hz, 1H), 2.85 (t, J = 6.3 Hz, 2H), 2.43 (t , J = 6.8 Hz, 2H)

Compounds of Examples 2 to 9 having the physical properties shown in Table 1 were prepared by performing a similar procedure to the preparation method described in Example 1 above.

Example 2: 3- (6-Chloro-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (2d)

Example 3: N-hydroxy-3 (6-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (3d)

Example 4: N-hydroxy-3- (7-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (4d)

Example 5: N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3yl) -propionamide (5d)

Example 6: 3- (6-t-butyl-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (6d)

Example 7: N-hydroxy-3- (2-oxo-2H-chromen-3-yl) -propionamide (7d)

Example 8: N-hydroxy-3- (3-oxo-3H-benzo [f] chromen-2-yl) -propionamide (8d)

Example 9: 3- (8-ethoxy-2-oxo-2H-chromen-3 -yl) -N-hydroxy-propionamide (9d)

Example Chemical structure NMR spectral data ( ¹ H or ¹³ C) 2 7.64-7.24 (m, 4H), 2.85 (t, J = 7.1 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H). 3 169.39, 162.29, 156.10, 147.52, 140.90, 127.27, 199.68, 118.87, 117.19, 109.60, 55.64, 30.90, 27.1 4 171.60, 163.95, 163.73, 156.28, 142.10, 129.92, 124.70, 114.38, 113.71, 101.31, 56.36, 32.06, 27.9 5 145.68, 140.42, 133.89, 131.55, 126.91, 126.44, 125.67, 118.68, 115.31, 98.12, 98.12, 65.01, 61.04, 19.65 6 171.53, 163.59, 152.59, 149.04, 142.35, 129.91, 128.18, 125.33, 120.29, 116.7, 35.43, 31.96, 31.71, 28.08 7 170.20, 162.75, 153.56, 141.41, 131.53, 128.08, 127.56, 125.04, 119.84, 116.62, 27.43, 23.77 8 170.01, 163.15, 153.22, 137.48, 133.06, 131.15, 129.62, 129.45, 128.77, 127.33, 126.70, 122.44, 116.90, 114.34, 31.97, 28.09 9 170.6`, 162.71, 146.91, 143.67, 141.84, 127.96, 125.17, 120.91, 119.77, 115.12, 65.6, 31.47, 27.57, 14.88

Example 10. Synthesis of 3- (6-bromo-2-oxo-2H-chromen-3-yl) -butyric acid (10i)

Step 1: 3-methyl-pentanedioic monomethyl ester (10f)

Starting material (10e) (107 mg, 0.61 mmol) was dissolved in methanol solvent and then barium hydroxide (52 mg, 0.30 mmol) was added to this solution. After stirring this solution at room temperature for 12 hours, the solvent was distilled at low pressure and the residue was dissolved in 10% hydrochloric acid solution and organic solvent ethyl acetate to make the solution pH 2 to 3, and then the solution was diluted with organic solvent ethyl acetate. The mixture was extracted, dried over anhydrous sodium sulfate, filtered, and the obtained solution was distilled at low pressure. The residue was purified by column chromatography (silica gel column, eluent dichloromethane / methanol = 10/1) to give 60% of compound (10f). Obtained in yield (60 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 3.67 (s, 3H), 2.48-2.25 (m, 5H), 1.04 (d, J = 6.3 Hz, 3H)

Step 2. Synthesis of 4-chlorocarbonyl-3-methyl-butyric acid methyl ester (10 g)

The first step (10f) (26 mg, 0.16 mmol) was dissolved in a dichloromethane solvent, followed by addition of oxalyl chloride (41 mg, 0.32 mmol) and a catalytic amount of dimethyl formamide, and the solution was kept at room temperature for 1 hour. After stirring, the solvent was removed at low pressure and used directly in the next reaction.

Step 3. Synthesis of 3- (6-bromo-2-oxo-2H-chromen-3-yl) -butyric acid methyl ester (10 h)

Compound (10g) obtained in the second step and compound (1a) of Scheme 1 were obtained by the operation of the first and second steps of Example 1 in 20% yield (20 mg).

¹³ C-NMR (CDCl ₃ , 400 MHz) δ 172.2, 151.8, 136.7, 133.6, 133.5, 129.8, 120.8, 118.1, 116.8, 51.6, 39.0, 32.2, 18.8

Step 4. Synthesis of 3- (6-bromo-2-oxo-2H-chromen-3-yl) -butyric acid (10i)

The compound (10h) (100 mg, 0.31 mmol) obtained in the second step was dissolved in a methanol solvent, barium hydroxide (52 mg, 0.61 mmol) was added thereto, stirred at room temperature for 8 hours, and the solvent was distilled off at low atmospheric pressure. . The residue was dissolved in 10% hydrochloric acid solution to pH 3, and then the organic material was extracted using ethyl acetate, an organic solvent, dried over anhydrous magnesium sulfate and filtered. The solution thus obtained was distilled at low atmospheric pressure and the residue was then subjected to column chromatography method (silica gel column, eluent dichloromethane / methanol = 10/1) to obtain compound (10i) in 90% yield (86 mg). .

¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.80 (d, J = 2.3 Hz, 1H), 7.74 (s, 1H), 7.64 (dd, J = 8.9, 2.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 3.38-3.33 (m, 1H), 2.76 (dd, J = 22.4, 6.8 Hz, 1H), 2.53 (dd, J = 15.7, 7.7 Hz, 1H), 1.31 (d, J = 6.9 Hz, 3H)

Example 11 Synthesis of N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -butylamide (11j)

Compound (11h) (100 mg, 0.38 mmol) obtained in the third step of Example 10 was added as a methanol solvent, and 1.7 mol of potassium hydroxyamine solution (34 μL, 0.8 mmol) was added thereto at room temperature for 1 hour. After stirring, the reaction was terminated with acetic acid and the resulting solution was distilled at low atmospheric pressure to obtain a residue, which was purified by column chromatography (silica gel column, eluent: methanol / chloroform = 1/10) to obtain 70% of the title compound. Obtained in (70 mg).

¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.69 (s, 1 H), 7.38 (s, 1 H), 7.35 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 3.36-3.30 (m, 1H), 2.56 (dd, J = 13.7, 6.6 Hz, 1H), 2.39 (s, 3H), 2.33 (dd, J = 13.6, 7.7 Hz, 1H), 1.30 (d, J = 6.8 Hz, 3H)

Example 12 Synthesis of N-hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide (12q)

Step 1. Synthesis of 2- (diethoxy-phosphoryl) -pentanedioic acid diethyl ester (12 l)

Compound (k) (1 g, 4.46 mmol) was dissolved in tetrahydrofuran solvent, and sodium hydride (196 mg, 4.91 mmol) was added thereto, stirred for 30 minutes in an ice bath, and ethyl acrylate (491 mg, 4.91 mmol) was added, followed by stirring for 4 hours, and the reaction was terminated with distilled water. The organics were extracted with organic solvent ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The resulting solution was distilled at low pressure and the residue was purified by column chromatography (silica gel column, eluent ethyl acetate / hexane = 2/1). (12l) was obtained in 82% yield (1.18 g).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 4.25-4.10 (m, 8H), 3.23-3.01 (m, 1H), 2.62-2.10 (m, 4H), 1.36-1.18 (m, 12H)

Step 2. Synthesis of 2- [2- (t-butyl-dimethyl-silanyloxy) -5-methyl-benzylidene] -pentanedioic acid diethyl ester (12n)

The first stage compound (12l) (700 mg, 2.16 mmol) was dissolved in tetrahydrofuran solvent, and sodium hydride (114 mg, 2.59 mmol) was added thereto, stirred for 30 minutes in an ice bath, and then compound (12m) in this solution. ) (561 mg, 2.37 mmol) was added thereto, stirred at room temperature for 12 hours, and the reaction was terminated with distilled water. The organics were extracted with organic solvent ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the resulting solution was distilled at low pressure and the residue was purified by column chromatography (silica gel column, eluent ethyl acetate / hexane = 1/10). (12n) was obtained in 55% yield (482 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.84 (s, 1 H), 7.06 (s, 1 H), 6.99 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.09 (q, J = 7.3 Hz, 2H). 2.81 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 8.6 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.96 (s, 9H), 0.14 (s, 6H)

Step 3. 2- [2- ( t -Butyl-dimethyl-silanyloxy) -5-methyl-benzylidene] -4-ethyl-pentanedioic acid diethyl ester (12o)

After dissolving the second compound (12n) (64 mg, 0.16 mmol) in a tetrahydrofuran solvent, 1 mol of LDA solution (173 μl, 0.17 mmol) was added to the solution at -78 ° C and stirred for 1 hour. After adding ethyl iodide to the solution and stirring at -78 ℃ for 30 minutes, the temperature was slowly raised to room temperature and stirred for another hour. After completion of the reaction with distilled water, the organic material was extracted with organic solvent ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the resulting solution was distilled at low atmospheric pressure. The residue was purified by column chromatography (silica gel column, eluent ethyl acetate / hexane =). 1/10) was used to obtain compound (12o) in 25% yield (17 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.81 (s, 1H), 7.11 (s, 1H), 6.98 (dd, J = 8.2, 2.0Hz, 1H), 6.69 (d, J = 8.2Hz, 1H) , 4.23 (qd, J = 7.1, 1.7 Hz, 2H), 4.07-3.99 (m, 2H, 2.82 (dd, J = 13.6, 7.8 Hz, 1H), 2.68 (dd, J = 13.6, 6.9 Hz, 1H) , 2.63-2.56 (m, 1H), 2.27 (s, 3H), 1.62-1.41 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H), 0.96 (s, 9H), 0.80 (t, J = 7.4 Hz, 3H), 0.14 (d, J = 7.1 Hz, 6H)

Step 4. Synthesis of N-hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide (12q)

The third step (12o) (17 mg, 0.04 mmol) of the third step was dissolved in tetrahydrofuran organic solvent, and then converted into phenol using 1 mol solution of tetrabutylammonium fluoride (47 μL, 0.05 mmol). Then, the title compound was synthesized in the same manner as in the second and third steps of Example 1.

¹ H-NMR (CD ₃ OD, 400MHz) δ 7.64 (s, 1H), 7.36 (d, J = 7.2Hz, 2H), 7.20 (d, J = 8.8Hz, 1H), 2.76-2.65 (m, 2H ), 2.46-2.40 (m, 1H), 2.38 (s, 3H), 1.72-1.52 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).

Compounds of Example 13 having physical properties as shown in Table 2 were prepared by performing a preparation process similar to the preparation method described in Example 12.

Example 13. N-hydroxy-2-methyl-3- (2-oxo-2H-chromen-3-yl) propionamide (13q)

Example Chemical structure NMR spectral data ( ¹ H or ¹³ C) 13 ¹³ C-NMR (CD ₃ OD, 400 MHz) δ 174.8, 163.4, 154.7, 142.6, 132.3, 129.1, 127.6, 125.7, 120.9, 117.2, 37.6, 36.2, 18.3.

Example 14 Synthesis of N-hydroxy-3- (6-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (14 ×)

Step 1. Synthesis of 5- (t-butyl-dimethyl-silanyloxy) -2-hydroxy-benzaldehyde (14s)

Compound (14r) (73 mg, 0.53 mmol) was dissolved in dichloromethane solvent, and TBSCl (80 mg, 0.53 mmol) and imidazole (43 mg, 0.64 mmol) were added and stirred at room temperature for 8 hours, followed by saturated ammonium chloride. The reaction was terminated with a solution. The organic material was extracted with organic solvent ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solution thus obtained was distilled at low atmospheric pressure, and the residue was then subjected to column chromatography (silica gel column, eluent ethyl acetate / hexane = 1/4) to obtain compound (14s) in 90% yield (120 mg).

¹ H-NMR (CDCl ₃ , 200 MHz) δ 10.61 (s, 1H), 9.78 (s, 1H), 7.06-6.86 (m, 3H), 0.97 (s, 9H), 0.16 (s, 6H)

Step 2. Synthesis of 3- [6- (t-butyl-dimethyl-silanyloxy) -2-oxo-2H-chromen-3-yl] -propionic acid methyl ester (14 u)

Compound (14u) is obtained by using the first step (14s) and the first step and the second step of Example 1.

¹ H-NMR (CDCl ₃ , 200 MHz) δ 7.58 (s, 1 H), 7.20-6.89 (m, 3 H), 3.65 (s, 3 H), 2.84 (t, J = 6.8 Hz, 2H), 0.97 (s, 9H), 0.16 (s, 6H)

Step 3. Synthesis of Synthesis of 3- (6-hydroxy-2-oxo-2H-chromen-3-yl) -propionic acid methyl ester (14v)

After dissolving the compound (14u) (72 mg, 0.2 mmol) in the second step in a tetrahydrofuran solvent, 1 mole solution of tetrabutylammonium fluoride (250 μL, 0.25 mmol) was added thereto, and stirred at room temperature for 10 minutes. The reaction was terminated with a saturated ammonium chloride solution and the organic material was extracted using an organic solvent ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The solution thus obtained was distilled at low atmospheric pressure, and the residue was then subjected to column chromatography method (silica gel column, eluent ethyl acetate / hexane = 1/1) to obtain compound (14v) in 90% yield (44.6 mg).

¹ H-NMR (CDCl ₃ , 200 MHz) δ 7.59 (s, 1 H), 7.30-6.99 (m, 3 H), 3.73 (s, 3 H), 2.86 (t, J = 6.8 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H)

Step 4. Synthesis of 3- (6-methoxy-2-oxo-2H-chromen-3-yl) -propionic acid methyl ester (14w)

The third step (14v) (20 mg, 0.08 mmol) was dissolved in organic solvent acetone, followed by addition of methyl iodide (7 μL, 0.10 mmol) and potassium carbonate (12 mg, 0.09 mmol) and 12 at 60 ° C. After stirring for an hour, the temperature was slowly lowered to room temperature, and then the reaction was terminated with distilled water. The organic material was extracted using an organic solvent ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the obtained solution was distilled at low pressure. The residue was purified by column chromatography (silica gel column, eluent ethyl acetate / hexane = 1/1). Compound (14w) was obtained in 57% yield (12 mg).

¹ H-NMR (CDCl ₃ , 200 MHz) δ 7.53 (s, 1 H), 7.24-6.85 (m, 3 H), 3.64 (s, 3 H), 2.86 (t, J = 7.3 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H)

Step 5. Synthesis of N-hydroxy-3- (6-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (14 ×)

The title compound was synthesized in the same manner as in the third step of Example 1.

¹ H-NMR (CD ₃ OD, 400MHz) δ 7.65 (s, 1H), 7.23-6.96 (m, 3H), 3.81 (s, 3H), 2.84 (t, J = 7.3Hz, 2H), 2.42 (t , J = 7.3 Hz, 2H)

Compounds of Examples 15 to 19 having the physical properties shown in Table 3 were prepared by performing a preparation process similar to the preparation method described in Example 14.

Example 15: 3- (6-Ethoxy-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (15 ×)

Example 16: 3- (6-benzyloxy-2-oxo-2 H -Chromen-3-yl)- N -Hydroxypropionamide (16x)

Example 17: N -Hydroxy-3- (2-oxo-6-phenethyloxy-2 H -Chromen-3-yl) -propionamide (17x)

Example 18: N -Hydroxy-3- (2-oxo-6- (3-phenyl-propoxy) -2 H -Chromen-3-yl] -propionamide (18x)

Example 19: N -Hydroxy-3- (2-oxo-6- (3-phenyl-butoxy) -2 H -Chromen-3-yl] -propionamide (19x)

Example Chemical structure NMR spectral data ( ¹ H or ¹³ C) 15 ¹ H-NMR (CD ₃ OD, 400 MHz) δ7.64 (s, 1H), 7.23-6.95 (m, 3H), 4.03 (q, J = 6.8 Hz, 2H), 2.84 (t, J = 7.3 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 1.39 (t, J = 7.3 Hz, 3H). 16 .47 (t, J = 7.1 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H), 5.09 (s, 3H), 6.98 (s, 1H), 7.12 (dd, J = 2.9, 9.1 Hz, 1H), 7.20-7.44 (m, 6H), 7.57 (s, 1H) 17 2.44 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H), 4.22 (t, J = 6.8 Hz, 2H), 7.08 ( s, 3H), 7.11 (dd, J = 2.9, 9.1 Hz, 1H), 7.19-7.31 (m, 6H), 7.70 (s, 1H) 18 2.10 to 2.14 (m, 2H), 2.49 to 2.59 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 3.96 (t, J = 6.2 Hz , 2H), 6.86 (s, 1H), 7.05 (dd, J = 2.5, 9.1 Hz, 1H), 7.20-7.36 (m, 6H), 7.55 (s, 1H) 19 1.84 (br s, 2H), 2.48-2.90 (m, 8H), 3.97 (br s, 1H), 6.87 (s, 1H), 7.01-7.04 (m, 1H), 7.17-7.38 (m, 6H), 7.56 (s, 1 H)

Example 20 Synthesis of 2-benzyl-N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (20af)

Step 1. Synthesis of 2-benzyl-acrylic acid ethyl ester (20z)

After dissolving Compound (20y) (272 mg, 1.16 mmol) in organic solvent ethanol, Eshmosser salt (537 mg, 2.90 mmol) was added and the solution was stirred at 65 DEG C for 8 hours, and the organic solvent was stirred at low pressure. Distilled. The residue was dissolved in organic solvent diethyl ether, the organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and the resulting solution was distilled at low atmospheric pressure and the residue was purified by column chromatography (silica gel column, eluent ethyl). Acetate / hexane = 1/10) gave compound (20z) in 82% yield (182 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.33-7.19 (m, 5H), 6.25 (d, J = 0.5 Hz, 1H), 5.46 (d, J = 1.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H)

Step 2. Synthesis of 2-benzyl-4- (diethoxy-phosphoryl) -pentanedioic acid diethyl ester (20aa)

Triethyl phosphonoacetate (210 mg, 0.94 mmol) was dissolved in tetrahydrofuran solvent, sodium hydride (46 mg, 1.13 mmol) was added and stirred in an ice bath for 30 minutes, and then the solution of the compound of the first step ( 20z) (182 mg, 0.94 mmol) was added and stirred at room temperature for 4 hours. After completion of the reaction with distilled water, the organic material was extracted with organic solvent ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the remaining solution was distilled at low atmospheric pressure. The residue was purified by column chromatography (silica gel column, eluent ethyl acetate / hexane). = 2/1) was used to give the compound (20aa) in 85% yield (331 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.17-7.02 (m, 5H), 4.09-3.91 (m, 8H), 3.00-2.55 (m, 4H), 2.30-1.91 (m, 2H), 1.22-1.12 (m, 9H), 1.02 (td, J = 7.2, 1.4 Hz, 3H)

Step 3. Synthesis of 2-benzyl-4- (2-benzyloxy-5-methyl-benzylidene) -pentanedioic acid diethyl ester (20ad)

The second step (20aa) (314 mg, 0.76 mmol) was dissolved in organic solvent tetrahydrofuran, sodium hydride (37 mg, 0.91 mmol) was added on an ice bath, and the solution was stirred for 30 minutes on an ice bath. (ac) (515 mg, 2.28 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction with distilled water, the organic material was extracted with organic solvent ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the organic solvent was distilled at low pressure. The residue was purified by column chromatography (silica gel column, eluent ethyl acetate / hexane = 1/20) to give compound (20ad) in 67% yield (248 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.82 (s, 1H), 7.36-6.80 (m, 13H), 5.05 (s, 2H), 4.24 (qd, J = 7.1, 1.8Hz, 2H), 4.07- 3.99 (m, 2H), 2.82-2.68 (m, 3H), 2.29 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H)

Step 4. Synthesis of 2-benzyl-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionic acid ethyl ester (20ae)

The third step (20ad) (248 mg, 0.51 mmol) was dissolved in organic solvent dichloromethane, and 1 mole solution of tribromo boron (1.3 mL, 1.53 mmol) was added at -78 ° C, and the reaction temperature was-. After raising to 20 ° C., the mixture was stirred for 1 hour, and then stirred again at room temperature for 6 hours. After completion of the reaction with distilled water in an ice bath, the organic material was extracted with an organic solvent, ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the resulting solution was distilled at a low pressure. Hexane = 1/3) was used to give the compound (20ae) in 48% yield (86 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.42 (s, 1H), 7.26-7.14 (m, 8H), 3.92 (qd, J = 8.0, 0.8 Hz, 2H), 3.27-3.17 (m, 1H), 3.02-2.72 (m, 4H), 2.35 (s, 3H), 0.96 (t, J = 7.1 Hz, 3H).

Step 5. Synthesis of 2-benzyl-N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (20af)

The compound was synthesized in the same manner as in the third step of Example 1.

¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.62 (s, 1H), 7.33-7.15 (m, 8H), 2.99-2.76 (m, 5H), 2.36 (s, 3H).

Example 21 Synthesis of N-hydroxy-3- (4-methoxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (21aj)

Step 1. Synthesis of 3- (4-hydroxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionic acid methyl ester (21ah)

Compound (21ag) (500 mg, 2.83 mmol) was dissolved in organic solvent methanol in 37% aqueous formaldehyde solution (300 mg, 3.70 mmol), ammonium acetate (240 mg, 3.11 mmol) and meldum acid (450 mg, 3.11 mmol) was added. After stirring the solution at 65 ° C. for 6 hours, the solvent was distilled at low pressure and the residue was purified by column chromatography (silica gel column, eluent dichloromethane / methanol = 10/1). Obtained in% yield (371 mg).

¹ H-NMR (CD ₃ OD, 300 MHz) δ 7.65 (s, 1 H), 7.29 (dd, J = 8.3, 1.6 Hz, 1H), 7.07 (d, J = 3.3 Hz, 1H), 5.01 (brs, 1H ), 3.66 (s, 3H), 2.79 (t, J = 7.3 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.35 (s, 3H)

Step 2. Synthesis of 3- (4-methoxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionic acid methyl ester (21ai)

The first step (21ah) (80 mg, 0.30 mmol) was dissolved in a solvent in which benzene and methanol were mixed 8 to 2, and then 1 mole solution of TMS-diazo methane (360 μL-450 μL, 1.2 mmol-1.5 mmol) was dissolved. ) Was added at room temperature for 10 minutes, the organic solvent was distilled at low pressure, and the residue was purified by column chromatography (silica gel column, eluent ethyl acetate / hexane = 1/1). Obtained in 67% yield (56 mg).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.46 (d, J = 1.3 Hz, 1H), 7.30-7.29 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.01 (d, J = 2.2 Hz, 3H), 3.67 (d, J = 2.2 Hz, 3H), 2.93 (td, J = 7.1, 2.0 Hz, 2H), 2.66 (td, J = 6.5, 1.9 Hz, 2H), 2.42 (s, 3H)

Step 3. Synthesis of N-hydroxy-3- (4-methoxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (21aj)

The compound was synthesized in the same manner as in the third step of Example 1.

¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.57 (s, 1 H), 7.40 (dd, J = 8.5, 1.9 Hz 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 4.05 (s, 3H) , 3.67 (d, J = 2.2 Hz, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.42 (s, 3H), 2.39 (t, J = 8.0 Hz, 2H)

Compounds of Examples 22 to 24 having the physical properties shown in Table 4 were prepared by performing a similar procedure to the preparation method described in Example 21.

Example 22: 3- (4-ethoxy-6-methyl-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (22j)

Example 23 N-hydroxy-3- (4-isopropoxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (23j)

Example 24: 3- (4-benzyloxy-6-methyl-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (24j)

Example Chemical structure NMR spectral data ( ¹ H or ¹³ C) 22 ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.54 (s, 1H), 7.40 (dd, J = 8.4, 1.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.23 (q, J = 7.0 Hz, 2H), 2.89 (t, J = 7.4 Hz, 2H), 2.42 (s, 3H), 2.38 (t, J = 8.0 Hz, 2H), 1.52 (t, J = 7.0 Hz, 3H) . 23 ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.54 (s, 1H), 7.40 (dd, J = 8.4, 1.7 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.71-4.65 ( m, 1H), 2.89 (t, J = 7.7 Hz, 2H), 2.42 (s, 3H), 2.38 (t, J = 7.7 Hz, 2H), 1.41 (d, J = 6.1 Hz, 6H). 24 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 7.50-7.24 (m, 8H), 5.23 (s, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.45 (t, J = 10.4 Hz, 2H), 2.38 (s, 3H).

Example 25. N -Hydroxy-4- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -butylamide (25at)

Step 1: Synthesis of hexanedioic acid ethyl ester 2-formyl-4-methoxy-phenyl ester (25aq)

4-methoxy-2-hydroxy-benzaldehyde (100 mg, 0.657 mmol), adipic acid monoethyl ester (137.3 mg, 0.788 mmol), 4-dimethylaminopyridine (96 mg, 0.788 mmol), triethylamine (0.1 ml , 0.788 mmol) was dissolved in acetonitrile (1 ml) at room temperature under nitrogen, and then slowly added 1- (3-dimethylaminopropyl) -3-methylcarbodiimide hydrochloride (EDCI) for 3 hours at room temperature. Stirred. After completing the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent gives 1 N hydrochloric acid, saturated sodium carbonate, and was dissolved in ethyl acetate and washed with brine. The organic solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (150 mg, reaction yield: 75%, colorless liquid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26 (t, J = 7.2 Hz, 3H), 1.76-1.80 (m, 4H), 2.38 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 3.84 (s, 3H), 4.14 (dd, J = 14.4, 7.2 Hz, 2H), 7.09 (d, J = 8.8 Hz, 1H) 7.15 (dd, J = 8.8, 2.8 Hz, 1H ), 7.34 (d, J = 2.8 Hz, 1H), 10.06 (s, 1H)

Step 2: Synthesis of 4- (6-methoxy-2-oxo-2H-chromen-3-yl) -butyric acid ethyl ester (25ar)

Compound (25aq) (100 mg, 0.32 mmol) was dissolved in toluene (1 ml) and 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU; 0.043 ml, 0.292 mmol) was added. After refluxing for 3 hours, the solvent was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (28 mg, reaction yield; 32%, colorless liquid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26 (t, J = 7.2 Hz, 3H), 1.95-2.03 (m, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 3.84 (s, 3H), 4.13 (dd, J = 14.4, 7.2 Hz, 2H), 6.88 (d, J = 2.8 Hz, 1H) 7.04 (dd, J = 8.8, 2.8 Hz, 1H ), 7.21 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H)

Step 3: 4- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -butyric acid (25as)

Compound (25ar) (25mg, 0.086mmol) was dissolved in methanol (1ml), 1ml 1M sodium hydroxide solution was added and stirred at room temperature for 2 hours. After completion of the reaction, acidified to pH = 3 with 2M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (20mg, reaction yield: 90%, white solid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.95-2.03 (m, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 3.84 (s, 3H) , 6.89 (d, J = 2.8 Hz, 1H) 7.06 (dd, J = 8.8, 2.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H)

Step 4:  N -Hydroxy-4- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -butylamide (25at)

Compound 25as (50 mg, 0.190 mmol), pentafluorophenol (39 mg, 0.209 mmol) and 4-dimethylaminopyridine (25 mg, 0.209 mmol) were dissolved in dichloromethane (1 ml) at room temperature under nitrogen, followed by 1- (3 -Dimethylaminopropyl) -3-methylcarbodiimide hydrochloride (EDCI; 40mg, 0.209mmol) was added slowly and stirred at room temperature for 2 hours. After completing the reaction the reaction solution was concentrated under reduced pressure, a 1 N hydrochloric acid to a dried solvent, back over anhydrous sodium sulfate gave saturated sodium carbonate, washed with brine. The mixture was dissolved in dichloromethane (1 ml) without purification, triethylamine (0.1 ml, 0.76 mmol) NH ₂ OH.HCl (52.8 mg, 0.76 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was washed with saturated ammonium chloride solution, the organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Purification by column chromatography (dichloromethane / methanol = 9/1) afforded the title compound (15 mg, reaction yield: 26%, white solid).

¹ H-NMR (400 MHz, CD ₃ OD) δ 1.93-1.98 (m, 2H), 2.19 (t, J = 7.2 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 3.85 (s, 3H ), 7.05 (d, J = 2.8 Hz, 1H) 7.10 (dd, J = 8.8, 2.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H)

Example 26. 5- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -pentanoic acid hydroxyamide (26at)

Step 1: Synthesis of Pimelic Acid Dimethyl Ester (26an)

Pimelic acid (1 g, 6.24 mmol) was dissolved in methanol (15 ml) and refluxed for 12 hours with the addition of a catalytic amount of sulfuric acid. The solvent of the reaction mixture was removed by concentration under reduced pressure, dissolved in ethyl acetate, the organic solvent layer was washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (1 g, reaction yield: 85%, colorless liquid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.21-1.36 (m, 2H), 1.55-1.65 (m, 4H), 2.61 (t, J = 7.2 Hz, 4H), 3.60 (s, 6H)

Step 2: Synthesis of Heptanedioic Acid Monomethyl Ester (26ao)

Compound 26an (700mg, 3.72mmol) was dissolved in methanol (10ml), 1N potassium hydroxide aqueous solution (3.6ml) was added dropwise and stirred at room temperature for 1 hour. The resulting reaction mixture was acidified with 2N hydrochloric acid (pH = 3), extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (500 mg, reaction yield: 77%, white solid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.21-1.36 (m, 2H), 1.55-1.65 (m, 4H), 2.44-2.33 (m, 4H), 3.61 (s, 3H)

Step 3: 5- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -pentanoic acid hydroxyamide (26at)

The title compound (20 mg, reaction) in the same manner as the synthesis of N -hydroxy-4- (6-methoxy-2-oxo- 2H -chromen-3-yl) -butylamide using compound (26ao) as a starting material Yield: 38%, white solid).

¹ H-NMR (400 MHz, CD ₃ OD) δ 1.63-1.78 (m, 4H), 2.15 (t, J = 7.2H, 2H), 2.55 (t, J = 7.2, 2H), 3.83 (s, 3H) , 7.08-7.12 (m, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H)

Compounds of Example 27 having the physical properties shown in Table 5 were prepared by performing a preparation procedure similar to the preparation method described in Example 26.

Example 27 N-hydroxy-2- (6-methoxy-2-oxo-2H-chromen-3-yl) -acetamide (27at)

Example Chemical structure NMR spectral data ( ¹ H or ¹³ C) 27 249.22 (M +)

Example 28. N -Hydroxy-3- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -acrylamide (28ay)

Step 1: Synthesis of Glutaconic Acid Diethyl Ester (28av)

Glutaconic acid (1 g, 9.7 mmol) was dissolved in ethanol (20 ml), and the title compound (1.3 g, reaction yield: 90%, white solid) was obtained in the same manner as in Example 5.

Step 2: 3- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -acrylic acid ethyl ester (28aw)

2-hydroxy-5-methoxybenzaldehyde (300 mg, 2 mmol) and glutaconic acid diethyl ester (372 mg, 2 mmol) were dissolved in ethanol (10 ml) and a catalytic amount of piperidine was added dropwise. The reaction was carried out at reflux for 6 hours. The solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (280 mg, reaction yield: 51%, yellow solid).

¹ H-NMR (400 MHz, CDCl ₃ ) 1.33 (t, J = 6.8 Hz, 3H), 3.86 (s, 3H), 4.27 (dd, J = 14, 6.8 Hz, 2H), 6.95 (d, J = 3.2 Hz, 1H), 7.10 (d, J = 15.6 Hz, 1H), 7.16 (dd, J = 9.2, 3.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 16.4 Hz, 1H), 7.82 (s, 1H)

Step 3: 3- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -acrylic acid (28ax)

Compound (28aw) (55 mg, 1.2 mmol) was obtained in the same manner as the third step of Example 25, to obtain the title compound (45 mg, reaction yield: 92%, yellow solid).

Step 4: N -Hydroxy-3- (6-methoxy-2-oxo-2 H Synthesis of -chromen-3-yl) -acrylamide (28ay)

Compound (28ax) (50 mg, 0.20 mmol) was obtained in the same manner as in Step 4 of Example 25, to obtain the title compound (12 mg, reaction yield: 38%, yellow solid).

¹ H-NMR (400 MHz, DMSO) 3.81 (s, 3H), 7.03 (d, J = 15.6 Hz, 1H), 7.23-7.39 (m, 4H), 8.30 (s, 1H), 9.12 (s, 1H) , 10.95 (s, 1H)

Example 29. N -Hydroxy-3- (6-methoxy-2-oxo-2 H Synthesis of -thiochromen-3-yl) propionamide (29bd)

Step 1: Synthesis of 4- (2-formyl-4-methoxyphenylsulfanylcarbonyl) butyric acid methyl ester (29bb)

4-methoxybenzenethiol (1g, 7.13mmol) was dissolved in dried hexane (10ml), TMEDA (2.37ml, 15.67mmol) was added and the temperature was lowered to 0 ° C to n -butyllithium (6.27ml, 15.69mmol) It was slowly put up to room temperature and reacted for one day. The reaction mixture was lowered back to 0 ° C., added DMF (1.10 ml, 14.26 mmol), and reacted at room temperature for 10 hours. The reaction was terminated with cold ice water, washed with 1N HCl, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. Without purification, the mixture was dissolved in dried dichloromethane (2 ml) and lowered to 0 ° C., followed by methyl-5-chloro-5-oxo-valorate (0.98 ml, 7.13 mmol) and triethylamine (1.24 ml, 7.13 mmol). Was added and reacted at room temperature for 3 hours. The reaction was terminated with water, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (430 mg, reaction yield: 20%, yellow solid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.02 to 2.07 (m, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 3.69 (s, 3H) , 3.89 (s, 3H), 7.18 (dd, J = 2.9, 8.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 10.18 (s, 1H)

Step 2: 3- (6-methoxy-2-oxo-2 H Synthesis of -thiochromen-3-yl) propionic acid methyl ester (29bc)

Compound (29bb) (430 mg, 1.45 mmol) was dissolved in dried toluene (10 ml) and DBU (0.21 ml, 1.30 mmol) was added. After 3 hours, the solvent was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (424 mg, reaction yield: 98%, yellow solid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.67 (t, J = 7.1 Hz, 2H), 2.90 (t, J = 7.3 Hz, 2H), 3.66 (s, 3H), 3.87 (s, 3H), 7.05 ~ 7.09 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H)

Step 3: N -Hydroxy-3- (6-methoxy-2-oxo-2 H -Thiochromen-3-yl) propionamide (29bd)

Compound (29bc) (150 mg, 0.53 mmol) was dissolved in dried methanol (2 ml), and 1.76 M NH ₂ OH KCl (1.53 ml, 2.69 mmol) dissolved in methanol was added and reacted at room temperature for 1 hour. The reaction was terminated with cold ice water, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (35 mg, reaction yield: 24%, Yellow solid).

¹ H-NMR (400 MHz, CD ₃ OD) δ 2.40 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 3.87 (s, 3H), 7.16 (dd, J = 2.5 , 8.8 Hz, 2H), 7.28 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H)

Example 30. N Synthesis of -hydroxy-3- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) -propionamide (30 bm)

Step 1: Synthesis of 5-methoxy-2-nitro-benzaldehyde (30be)

5-hydroxy-2-nitro-benzaldehyde (7g, 41.88mmol) and potassium carbonate (8.7g, 62.8mmol) were dissolved in acetone (300ml), and iodine methane (5.3ml, 83.77mmol) was slowly added dropwise at room temperature. Stir for 24 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and then the organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (5 g, reaction yield: 65%, yellow solid).

¹ H-NMR (400MhH, CDCl ₃ ) δ 3.96 (s, 3H), 7.16 (dd, J = 8.8, 2.8Hz, 1H), 7.33 (d, J = 2.8Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 10.49 (s, 1H)

Step 2: Synthesis of 2- (5-methoxy-2-nitro-benzylidene) -malonic acid diethyl ester (30bf)

It was dissolved in compound 30be (12g, 66.24mmol) and diethylmalonate (15ml, 99.3mmol) acetic anhydride (100ml) and slowly added dropwise sodium bicarbonate (8.3g, 99.3mmol) for 18 hours at 100 ° C. Was stirred. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (14 g, reaction yield: 66%, colorless liquid) (Bioorg. Med. Chem. Lett., 13 , p1187, 2003).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.05 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 3.88 (s, 3H), 4.11 (dd, J = 14.4, 7.2 Hz, 2H), 4.34 (dd, J = 14.4, 7.2 Hz, 2H), 6.87 (d, J = 2.8 Hz, 1H), 6.97 (dd, J = 8.8, 2.8 Hz, 1H), 8.21 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H)

Step 3: Synthesis of 6-methoxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (30bg)

Compound (30bf) (14g, 43.3mmol) and iron (24g, 433mmol) were added to acetic acid (200ml) and stirred at 80 ° C for 12 hours. The terminated reaction mixture was filtered to remove iron and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 95: 5) to give the title compound (5.8 g, reaction yield: 54%, white solid) ( Heterocycles. , 53 , p2471, 2000).

¹ H-NMR (400Hhz, CDCl ₃ ) 1.44 (t, J = 7.2Hz, 3H), 3.98 (s, 3H), 4.45 (dd, J = 14.4, 7.2Hz, 2H), 7.05 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 8.56 (s, 1H), 11.64 (s, 1H)

Step 4: 3-hydroxymethyl-6-methoxy-1 H Synthesis of -quinolin-2-one (30bh)

Compound (30bg) (2 g, 8.09 mmol) was dissolved in tetrahydrofuran (60 ml), and LiAlH ₄ (300 mg, 8.09 mmol) was slowly added dropwise at 0 ° C, and stirred at room temperature for 2 hours. The mixture was terminated with water and 15% aqueous sodium hydroxide solution, filtered and the organic solvent layer was concentrated under reduced pressure. The residue obtained was purified by column chromatography (dichloromethane: methanol = 95: 5) to obtain the title compound (910 mg, reaction yield: 55%, white solid).

¹ H-NMR (400Hhz, CD ₃ OD) 3.85 (s, 3H), 4.67 (s, 2H), 7.15-7.19 (m, 2H), 7.29 (d, J = 8.8Hz, 1H), 7.95 (s, 1H)

Step 5: 3-bromomethyl-6-methoxy-1 H Synthesis of -quinolin-2-one (30bi)

Compound (30bh) (0.044ml, 0.31mmol) was dissolved in dimethylformamide (1ml), and PBr ₃ (0.030ml, 0.31mmol) was slowly added dropwise at 0 ° C, and stirred at room temperature for 3 hours. The reaction mixture was quenched with water, and then the solvent was concentrated under reduced pressure. The residue was washed with chloroform ethyl acetate to give the title compound (30 mg, reaction yield: 45%, white solid).

¹ H-NMR (400 MHz, CDCl ₃ ) 3.95 (s, 3H), 4.59 (s, 2H), 7.23 (d, J = 2.8 Hz, 1 H), 7.56 (dd, J = 8.8, 2.8 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1H), 8.51 (s, 1H)

Step 6: Synthesis of 2- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) methyl-malonic acid diethyl ester (30bj)

Diethylmalonate (1.13 ml, 7.46 mmol) was dissolved in tetrahydrofuran (10 ml) solution at 0 ° C. under nitrogen and sodium hydride (134 mg, 5.6 mmol) was slowly added dropwise. After stirring for 30 minutes, 3-bromomethyl-6-methoxy-1H-quinoline-2-one (1 g, 3.73 mmol) was dissolved in tetrahydrofuran (10 ml) and slowly added dropwise, followed by stirring at room temperature for 2 hours. . The reaction mixture was washed with water, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (1.8 g, reaction yield: 74%, white solid) (Bioorg., Chem. , 31 , p 80, 2003).

¹ H-NMR (400 MHz, CDCl ₃ ) 1.16-1.27 (m, 6H), 3.24 (d, J = 8 Hz, 2H), 3.85 (s, 3H), 4.11-4.21 (m, 5H), 6.94 (d, J = 2.8 Hz, 1H), 7.12 (dd, J = 8.8, 2.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 11.86 (s, 1H)

Step 7: Synthesis of 2- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) -propane-peroxic acid (30bk)

Compound (30bj) (1 g, 2.87 mmol) was dissolved in acetic acid (100 ml), HCl (70 ml), water (50 ml) solution and refluxed for 5 days. The solvent was concentrated under reduced pressure to obtain the title compound (1.1 g, white solid) (J. Amer., Chem. Soc., 122 , p12458, 2000).

Step 8: Synthesis of 2- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) -propionic acid methyl ester (30 bl)

Compound (30bk) (1.1 g) was obtained in the same manner as the first step of Example 26, to obtain the title compound (600 mg, two-step reaction yield: 81%, white solid).

¹ H-NMR (400 MHz, CDCl ₃ ) 2.80 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 3.71 (s, 3H), 3.85 (s, 3H), 6.59 ( s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 12.09 (s, 1H)

Step 9: N Synthesis of -hydroxy-3- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) -propionamide (30 bm)

Compound (30bl) (100mg, 0.53mmol) was dissolved in methanol (2ml), and 1.76M NH ₂ OH KCl (0.53ml, 0.95mmol) dissolved in methanol was added and reacted at room temperature for 1 hour. The reaction was terminated with cold ice water, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (10 mg, reaction yield: 20%, Yellow solid).

¹ H-NMR (400 MHz, CD ₃ OD) 2.42 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 3.81 (s, 3H), 7.03 (d, J = 2.4 Hz , 1H), 7.07 (dd, J = 8.8, 2.4 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H)

Example 31. N Synthesis of -hydroxy-3- (6-methoxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl) propionamide (31bo)

Step 1: Synthesis of 3- (6-methoxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl) propionic acid methyl ester (31bn)

Dry 3- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) propionic acid methyl ester (100 mg, 0.38 mmol) and K ₂ CO ₃ (80 mg, 0.57 mmol) Dissolved in DMF (2ml) and added methyl iodo (0.071ml, 1.14mmol) and reacted at room temperature for 18 hours. The reaction was terminated with cold ice water, washed with 1N hydrochloric acid, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (88 mg, reaction yield: 98%, white solid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.74 (t, J = 7.1 Hz, 2H), 2.96 (t, J = 7.3 Hz, 2H), 3.66 (s, 3H), 3.72 (s, 3H), 3.86 (s, 3H), 6.99 (s, 1H), 7.15 (dd, J = 2.9, 9.1 Hz, 1H), 7.25-7.28 (m, 1H), 7.55 (s, 1H)

Step 2: N Synthesis of -hydroxy-3- (6-methoxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl) propionamide (31bo)

Compound (31bn) (87.7 mg, 0.31 mmol) was tested in the same manner as in the third step of Example 29 to obtain the title compound (52 mg, reaction yield: 61%, white solid).

¹ H-NMR (400 MHz, CD ₃ OD) δ 2.44 (t, J = 7.3 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H), 3.72 (s, 3H), 3.83 (s, 3H), 7.13 (s, 1H), 7.20 (dd, J = 2.5, 9.1 Hz, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H)

Example 32. 3- (1-benzyl-6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)- N -Synthesis of hydroxy-propionamide (32bo)

Step 1: Synthesis of 3- (1-benzyl-6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) propionic acid methyl ester (32bn)

Examples of 3- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) propionic acid methyl ester (100 mg, 0.38 mmol) with benzyl bromide (0.13 ml, 1.14 mmol) Experiment in the same manner as in step 1 of 31, to obtain the title compound (99 mg, reaction yield: 75%, white solid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.76 (t, J = 7.3 Hz, 2H), 3.02 (t, J = 7.1 Hz, 2H), 3.67 (s, 3H), 3.82 (s, 3H), 5.55 (s, 2H), 6.98-7.01 (m, 2H), 7.15-7.31 (m, 6H), 7.60 (s, 1H)

Step 2: 3- (1-benzyl-6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)- N -Synthesis of hydroxy-propionamide (32bo)

Compound (32bn) (95 mg, 0.27 mmol) was tested in the same manner as in the third step of Example 29 to obtain the title compound (43 mg, reaction yield: 42%, white solid).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.56 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H), 3.79 (s, 3H), 5.50 (s, 2H), 6.96 ~ 6.99 (m, 2H), 7.10-7.27 (m, 6H), 7.63 (s, 1H),

Experimental Example 1. Measurement of TNF-α Converting Enzyme (TACE) Activity

Enzymatic activity of TACE (R & D Systems, Minneapolis, MN, USA) was synthesized at 25 ° C., Mca-Pro-Leu-Ala-Gln-Ala-Val-Dpa-Arg-Ser-Ser-Ser-Agr-NH ₂ (Mca: [7-methoxycoumarin-4-yl] acetyl Dpa: N- 3- [2,4-dinitrophenyl] -L-2,3-diaminopropionyl, R & D Systems, Minneapolis, MN, USA). The fluorescent material produced after the enzyme reaction was measured for fluorescence using a Perkin-Elmer spectrophotometer LS50B, and then the activity inhibition was measured in comparison with the non-pharmaceutical administration group. As a result of the enzymatic reaction, the Mca product, a fluorescence reactor, showed fluorescence, which was absorbed at the excitation wavelength of 324 nM and measured at 420 nM of fluorescence, which is closely related to the activity of the enzyme (see Table 6).

Experimental Example 2. Measurement of Cell Activity (TNF-α)

By measuring the amount of TNF-α accumulated in the cell culture, the ability of the compounds of the present invention to inhibit TNF-α production was examined. In this experiment, Raw 264.7 cells (ATTC, USA), one of the mouse macrophage cell lines, were used.

RAW 264.7 cells, the macrophage cell line of mice, were cultured in DMEM medium containing 5% fetal bovine serum (FBS). After incubating RAW 264.7 cells in a 96 well plate at a suitable concentration (1 × 10 ⁶ cells / ml to 5 × 10 ⁶ cells / ml) under culture conditions of 5% CO ₂ , 37 ° C., Appropriate concentrations of compound were treated with cells (0.1-10 μM). Cells were activated by treatment with lipopolysaccharide (final concentration 0.3 μg / ml) (Sigma, USA) while the cells were treated with the compound. Cell cultures were collected 24 hours after lipopolysaccharide and compound treatment. The amount of TNF-α present in the collected cell culture solution was quantified using an ELISA assay kit (Quantikine colorimetric sandwich ELISA assay kit, manufactured by R & D systems, USA). The experimental results are shown in Table 6 below (AA means IC ₅₀ 's <1, A means IC ₅₀ 's <5, B means IC ₅₀ 's <10 and C means IC ₅₀ 's> 10). ). As shown in Table 6 below, the effect of compounds on the production capacity of TNF-α from macrophages was measured. As a result, it was confirmed that the compounds of the present invention had excellent TNF-α production inhibitory activity.

Example TACE inhibitory activity TNF-α Inhibitory Activity One AA C 2 AA C 3 AA A 4 AA C 5 AA A 6 C C 7 AA A 8 C C 9 C C 10 C - 11 C - 12 AA AA 13 AA AA 14 AA AA 15 A C 16 A C 17 A C 18 A C 19 A C 20 AA AA 21 C C 22 C C 23 C C 24 C C 25 C C 26 C C 27 C C 28 C C 29 AA B 30 A - 31 A - 32 C -

The compound according to the present invention exhibits a strong inhibitory activity against tumor necrosis factor-α converting enzyme (TNF-α converting enzyme), whereby the composition comprising the same can be used as a medicament for the treatment of inflammatory diseases, especially arthritis.

Claims (7)

A compound of formula (I) or a pharmacologically acceptable salt thereof: (Ⅰ) Where X is -OH, -NHOH, or NHO-R ', R' is a lower alkyl group or benzyl group; n is an integer from 1 to 4; Y is O, S, or N; R ₁ is a hydrogen atom, a lower alkyl group or a benzyl group; R ₂ is C ₁ to C ₄ lower alkyl, C ₁ to C ₄ lower alkoxy; R ₃ to R ₆ are each independently a hydrogen atom, nitro, halogen, amine, acetamide, carboamide, sulfonamide group, C ₁ to C ₄ lower alkyl, C ₁ to C ₇ unsubstituted or substituted Alkoxy, and these substituents may be fused to each other to form a 3- to 5-membered aromatic ring of heteroaryl substituted with an aromatic or hetero atom, and R ″ is a 5- to 6-membered ring substituted with an aryl group or a hetero atom. . The method of claim 1, X is -OH, -NHOH, Y is oxygen atom or sulfur atom, R ₁ is a hydrogen atom, methyl or ethyl group, R ₂ is methyl, ethyl, methoxy or ethoxy, R ₃ to R ₆ is a hydrogen atom, a halogen, a C ₁ to C ₄ alkoxy or phenyl group substituted with a C ₁ to C ₇ alkoxy group or a ternary heteroaromatic compound formed by fusion of these substituents or pharmacology thereof Acceptable salts. The method of claim 1, 3- (6-bromo-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (1d), 3- (6-chloro-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (2d), N-hydroxy-3 (6-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (3d), N-hydroxy-3- (7-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (4d), N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3yl) -propionamide (5d), 3- (6-t-butyl-2-oxo-2H-chromen-3yl) -N-hydroxy-propionamide (6d), N-hydroxy-3- (2-oxo-2H-chromen-3yl) -propionamide (7d), N-hydroxy-3- (3-oxo-3H-benzo [f] chromen-2-yl) -propionamide (8d), 3- (8-ethoxy-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (9d), 3- (6-bromo-2-oxo-2H-chromen-3-yl) -butyric acid (10i), N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -butylamide (11j), Synthesis of N-hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide (12q), N-hydroxy-3- (6-methoxy-2-oxo-2H-chromen-3-yl) -propionamide (14x), 3- (6-ethoxy-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (15x), 3- (6-benzyloxy-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (16x), N-hydroxy-3- (2-oxo-6-phenethyloxy-2H-chromen-3-yl) -propionamide (17x), N-hydroxy-3- (2-oxo-6- (3-phenyl-propoxy) -2H-chromen-3-yl] -propionamide (18x), N-hydroxy-3- (2-oxo-6- (3-phenyl-butoxy) -2H-chromen-3-yl] -propionamide (19x), N-hydroxy-3- (4-methoxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (21aj), 3- (4-ethoxy-6-methyl-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (22j), N-hydroxy-3- (4-isopropoxy-6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (23j), 3- (4-benzyloxy-6-methyl-2-oxo-2H-chromen-3-yl) -N-hydroxy-propionamide (24j), N-hydroxy-4- (6-methoxy-2-oxo-2H-chromen-3-yl) -butylamide (25at), 5- (6-methoxy-2-oxo-2H-chromen-3-yl) -pentanoic acid hydroxyamide (26at), N-hydroxy-2- (6-methoxy-2-oxo-2H-chromen-3-yl) -acetamide (27at), N-hydroxy-3- (6-methoxy-2-oxo-2H-thiochromen-3-yl) propionamide (29bd), N-hydroxy-3- (6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) -propionamide (30 bm), N-hydroxy-3- (6-methoxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl) propionamide (31bo), 3- (1-benzyl-6-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl) -N-hydroxy-propionamide (32bo) or a pharmacologically acceptable salt thereof . A compound of formula (II): or a pharmacologically acceptable salt thereof: (Ⅱ) Where dotted line( ) Means a single bond or a double bond; X is -OH, -NHOH, or NHO-R ', R' is a lower alkyl group or benzyl group; Y is O, S, or N; R ₁ is a hydrogen atom, a lower alkyl group or a benzyl group; R ₂ is C ₁ to C ₄ lower alkyl, C ₁ to C ₄ lower alkoxy; R ₃ to R ₆ are each independently a hydrogen atom, nitro, halogen, amine, acetamide, carboamide, sulfonamide group, C ₁ to C ₄ lower alkyl, C ₁ to C ₇ unsubstituted or substituted Lower alkoxy, and these substituents may be fused together to form a 3- to 5-membered ring of heteroaryl substituted with an aromatic or hetero atom, and R ″ is a 5- to 6-membered ring substituted with an aryl group or a hetero atom; R ₇ to R ₉ are each independently a hydrogen atom, a lower alkyl group substituted with a C ₁ to C ₇ alkyl, aryl group or heteroaryl group, provided that they are not hydrogen atoms at the same time. The method of claim 4, wherein X is -OH, -NHOH, Y is oxygen atom or sulfur atom, R ₁ is a hydrogen atom, methyl or ethyl group, R ₂ is methyl, ethyl, methoxy or ethoxy, R ₃ to R ₆ is a hydrogen atom, a halogen, a C ₁ to C ₄ alkoxy or phenyl group substituted with a C ₁ to C ₇ alkoxy group or a three-membered heteroaromatic compound formed by fusion of these substituents, R ₇ to R ₉ is a group of compounds which are lower alkyl groups of C ₁ to C ₄ or a pharmacologically acceptable salt thereof. The method of claim 4, wherein N-hydroxy-2-methyl-3- (2-oxo-2H-chromen-3-yl) propionamide (13q), 2-benzyl-N-hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide (20af), N -hydroxy-3- (6-methoxy-2-oxo- 2H -chromen-3-yl) -acrylamide (28ay) or a pharmacologically acceptable salt thereof. A pharmaceutical composition for treating an inflammatory disease comprising the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof as an active ingredient.